Evolving to an Ideal Synthesis of Molnupiravir, an Investigational Treatment for COVID-19

Abstract

<p>Molnupiravir (MK-4482) is an investigational direct-acting antiviral agent that is under development for the treatment of COVID-19. Given the potential high demand for this compound, it was critical to develop a sustainable and efficient synthesis from commodity raw materials. The three-step route that we report here embodies the shortest possible synthesis to molnupiravir, and was enabled through the invention of a novel biocatalytic cascade and final condensation step. Each step occurs in over 95% yield and only utilizes widely available commodity reagents and simple operations. Compared to the initial route, the new route is 70% shorter, and approximately seven-fold higher in overall yield. <br></p>

Biocatalysis

“…The accessibility of obtaining biocatalysts through commercial sources or from synthetic genes is continuing to lower the barrier to entry for biosynthesis and the bottleneck for reaction screening is now often at the assay stage, where more label-free high-throughput analytical methods are needed 50 . Current successes for compounds such as islatravir 7 and molnupiravir 154 have demonstrated the application of biocatalysis to multistep syntheses of small molecules. The next challenges will be to extend the application scope to targets of increasing molecular complexity and size, as well as to decrease the time required to develop efficient biocatalytic industrial processes.…”

“…The final deoxyribose phosphate aldolase (DERA), phosphopentamutase (PPM) and purine nucleoside phosphorylase (PNP) steps were then run concurrently, and the equilibrium of these steps was pulled through to product formation by an orthogonal sucrose phosphorylase (SP) step that removed phosphate from the reaction mixture. The cascade synthesis of islatravir (and, more recently, of molnupiravir) 154 replaced alternative chemical routes to this drug that required more than double the step count with protecting group manipulations, thereby vastly improving the efficiency of synthesis.…”

“…These timescales are not fast enough to meet 'the need for speed' in industry 169 . A recent example of a three-step route including two enzymatic steps, which was developed in just 6 months, is the synthesis of the COVID-19 direct-acting antiviral molnupiravir 154 . Development of highly efficient biocatalysts by either rational or evolution techniques will be accelerated in the near future by expanding both the use of machine learning 170 and ultra-high-throughput screening 171 technologies for protein engineering.…”

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods

“…A more efficient synthesis was urgently required to address these two key synthetic challenges and to meet the antiviral therapy demand. We envisioned a shorter and more efficient route to uprifosbuvir starting from the inexpensive and readily available uridine 5, 10 which already contains all of the atoms in the nucleoside portion of the molecule, with the glaring -and challenging -exception of the tertiary alkyl chloride in the 2'position. We started out by exploring selective functionalization in the 2'-position in uridine.…”

Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19

“…If either of these treatments are found to be successful in larger studies, it is imperative that the global health community does all it can to push for fair prices and equitable access. Molnupiravir is a small molecule direct-acting antiviral and synthesis is straightforward so we estimate that as an oral formulation, production costs would be less than remdesivir [45,46]. Proxalutamide is also a small molecule drug (non-steroidal androgen receptor antagonist) and is unlikely to be complex or expensive to manufacture.…”